A Pilot Study in Rhesus Macaques to Assess the Treatment Efficacy of a Small Molecular Weight Catalytic Metalloporphyrin Antioxidant (AEOL 10150) in Mitigating Radiation-induced Lung Damage

Abstract

The objective of this pilot study was to explore whether administration of a catalytic antioxidant, AEOL 10150 (C48H56C15MnN12), could reduce radiation-induced lung injury and improve overall survival when administered after 11.5 Gy of whole thorax lung irradiation in a non-human primate model. Thirteen animals were irradiated with a single exposure of 11.5 Gy, prescribed to midplane, and delivered with 6 MV photons at a dose rate of 0.8 Gy min. Beginning at 24 h post irradiation, the AEOL 10150 cohort (n = 7) received daily subcutaneous injections of the catalytic antioxidant at a concentration of 5 mg kg for a total of 4 wk. All animals received medical management, including dexamethasone, based on clinical signs during the planned 180-d in-life phase of the study. All decedent study animals were euthanized for failure to maintain saturation of peripheral oxygen > 88% on room air. Exposure of the whole thorax to 11.5 Gy resulted in radiation-induced lung injury in all animals. AEOL 10150, as administered in this pilot study, demonstrated potential efficacy as a mitigator against fatal radiation-induced lung injury. Treatment with the drug resulted in 28.6% survival following exposure to a radiation dose that proved to be 100% fatal in the control cohort (n = 6). Computed tomography scans demonstrated less quantitative radiographic injury (pneumonitis, fibrosis, effusions) in the AEOL 10150-treated cohort at day 60 post-exposure, and AEOL 10150-treated animals required less dexamethasone support during the in-life phase of the study. Analysis of serial plasma samples suggested that AEOL 10150 treatment led to lower relative transforming growth factor-Beta-1 levels when compared with the control animals. The results of this pilot study demonstrate that treatment with AEOL 10150 results in reduced clinical, radiographic, anatomic, and molecular evidence of radiation-induced lung injury and merits further study as a medical countermeasure against radiation-induced pulmonary injury.

Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation

“…Detailed irradiation procedures and dosimetry methods were described previously (MacVittie et al 2012a; Garofalo et al 2014a; Garofalo et al 2014b). Briefly, NHP were exposed to WTLI or PBI/BM5.…”

“…All NHP received medical management during the study according to an Institutional Animal Care and Use Committee (IACUC)-approved protocol of triggers and treatments, as described previously (Farese et al 2012; MacVittie et al 2012a; Garofalo et al 2014a; Garofalo et al 2014b). Treatments were based on clinical signs and symptoms and included rehydration fluids, antibiotics, analgesics, antidiarrheals, antipyretics, antiemetics, cytoprotection for mucosal ulcers, corticosteroids, nutritional support, and blood transfusions.…”

“…NHP models and dose-response relationships of whole thorax lung irradiation (WTLI) and partial-body irradiation with approximate 5% bone marrow sparing (PBI/BM5) were established to investigate the DEARE as a characteristic of multi-organ injury. These models were used to study the efficacy of medical countermeasures against radiation to enhance survival and overall quality-of-life (Farese et al 2013; Farese et al 2014; Garofalo et al 2014b). Because of the similarity of NHP to humans, the NHP platform is unique in providing a closely relevant model to study RIF in multiple organs.…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

“…Promising radiation countermeasures under development for H-ARS have been tested in NHP for efficacy and pharmacokinetics/ pharmacodynamics. Some important radiation countermeasures tested for efficacy in the NHP model include G-CSF (filgrastim, Neupogen) (Farese et al 2013;, PEGylated G-CSF (PEGfilgrastim/Neulasta) (Hankey et al 2015), CBLB502 (Entolimod) (Krivokrysenko et al 2012(Krivokrysenko et al , 2015, interleukin-12 (HemaMax) (Basile et al 2012;GluzmanPoltorak et al 2014aGluzmanPoltorak et al , 2014b, AEOL 10150 (meso-porphyrin mimetic) (Garofalo et al 2014b), 5-Androstenediol (Stickney et al 2006(Stickney et al , 2007, amifostine (WR2721, Ethyol) (Geary et al 1989), B-190 (Vasin et al 2014) and c-tocotrienol (Singh et al 2016a). …”

Improvements in SOD mimic AEOL-10150, a potent broad-spectrum antioxidant

“…The AEOL-10150-treated group required less dexamethasone support during the survival phase of the study. Compared with the control cohort, the AEOL-10150 treatment group showed lower plasma TGF-β 1 levels [27]. …”